EP0632732B1 - Medikamenteninfusionspumpe - Google Patents

Medikamenteninfusionspumpe Download PDF

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Publication number
EP0632732B1
EP0632732B1 EP93906662A EP93906662A EP0632732B1 EP 0632732 B1 EP0632732 B1 EP 0632732B1 EP 93906662 A EP93906662 A EP 93906662A EP 93906662 A EP93906662 A EP 93906662A EP 0632732 B1 EP0632732 B1 EP 0632732B1
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EP
European Patent Office
Prior art keywords
cylinder
section
membrane
plunger
pump according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP93906662A
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English (en)
French (fr)
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EP0632732A1 (de
Inventor
Michael V. Wiernicki
Mark G. Scattergood
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Compagnie de Developpement Aguettant SA
Original Assignee
Compagnie de Developpement Aguettant SA
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Publication of EP0632732A1 publication Critical patent/EP0632732A1/de
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps
    • A61M5/14212—Pumping with an aspiration and an expulsion action
    • A61M5/14216—Reciprocating piston type

Definitions

  • the present invention relates to a medical liquid infusion pump.
  • Intravenous infusion is today an essential technique of medication in the case of serious pathologies, such as cancer for example.
  • the effectiveness of the treatments is directly linked to the prescribed doses, and limited by the level of toxicity of the active ingredients.
  • the precision of the injection is therefore an important criterion in the choice of the material used.
  • the injection of an active principle must, in order to respect the patient's biological rhythms, be carried out preferably at certain times of the day, the injection rate possibly being variable throughout the injection period to take into account the immediate effects of the active ingredient on the body.
  • a trend in current medicine is to evolve towards treatments at the patient's home, this being more particularly true for serious pathologies such as cancer and AIDS treatments, which require very high technicality in the hospital environment and follow-up at home. of the patient.
  • the crushing of the tube requires a large force which is obtained by a bulky and heavy roller system.
  • the motor must be dimensioned to allow these crushing forces to be obtained, which leads to significant weight. Motor energy consumption being important, its supply must be carried out by a series of bulky and heavy batteries, which constitute a contradiction with the very principle of the ambulatory character of the pump.
  • Another solution consists in using suction devices with cylinder and piston, such as that illustrated for example in DE-A-3 515 624, or devices of the syringe pump type, in which the piston of a syringe containing the product to be injected is driven by a stepping motor.
  • suction devices with cylinder and piston such as that illustrated for example in DE-A-3 515 624, or devices of the syringe pump type, in which the piston of a syringe containing the product to be injected is driven by a stepping motor.
  • the object of the invention is to provide a pump for infusion of medical liquids, with several channels, that is to say capable of allowing the simultaneous infusion of several medical liquids, with the possibility of mixing or not mixing these liquids with the interior of the pump, which is of a very small footprint, and of a reduced weight, while allowing a very high accuracy of the flow over a very wide flow range which can vary for example between 1 milliliter per day and 300 milliliters per hour, and which offers significant safety for the patient.
  • Another object of the invention is to provide an infusion pump which has a part ensuring the transfer of liquids, which is removably mounted on a control box and drive in movement of the pump.
  • the pump according to the invention is a pump in which the metering of each liquid is carried out by a cylinder and piston device.
  • the liquid is drawn into the dosing cylinder and then discharged from the delivery line to the infusion catheter.
  • the originality of this pump lies essentially in the fact that the two functions of non-return valves, arranged respectively upstream and downstream of the metering cylinder, are fulfilled by the membrane which is arranged between the first and second parts.
  • the vacuum created inside the metering cylinder results in a deformation of the membrane towards the center of the metering cylinder, allowing passage liquid from the cavity in the second part, between the disc it contains and the membrane, then inside the central orifice of the membrane to the metering cylinder.
  • first and second parts can be provided, in the first and second parts, several metering pumps, for example four pumps, this embodiment being very simple insofar as the first and second parts can be constituted for example by parallelepipedic plates made of a material synthetic such as polycarbonate.
  • this "sandwich" construction makes it possible to incorporate, on the exhaust ducts, all safety devices, such as air detection devices and overpressure devices.
  • the evacuation pipes can be formed in the first part, so as to open over their entire length in the face of the first part in abutment against the second part, or on the contrary be formed in the thickness of the first part, while by opening into the lumen arranged adjacent to a metering cylinder.
  • the disc arranged in the cavity of the second part comprises a cylindrical part of large diameter, extended in its central part and on the side of the cylinder by a cylindrical part of diameter smaller than that of the cylinder, the through holes being formed in the outer part and opening facing the cylinder.
  • This stepped structure improves the sealing conditions, since the support of the disc against the membrane is made according to several concentric edges.
  • this pump comprises a third part, in contact with the first part on the side opposite to the second part, and having bores extending the cylinders of the first part, a waterproofing membrane being mounted tightly between the first and third parts, the piston of each pump comprising two parts assembled to each other and arranged on either side of the waterproofing membrane, including the one located in the cylinder is made of a material compatible with the liquid to be conveyed, and the other part of which is intended for fixing the means for driving the piston.
  • the part of the piston located on the side of the third part, is made of a ferro-magnetic material, intended for fixing with the magnetized end of a moving drive rod.
  • each piston in two parts makes it possible to dissociate the functions of the piston, by providing the part located inside the metering cylinder with the function of suction and compression of the liquid contained in this cylinder, and by providing the part located on the other side of the membrane, the only function of fixing the piston drive means.
  • a material which is not necessarily compatible with the liquid conveyed and which can for example be a ferro-magnetic material allowing a immediate and reversible fixing of this part of the piston with the magnetic end of a moving drive rod of this piston.
  • the three parts and their intermediate membranes are assembled one on the other and form an independent functional cassette, intended to be removably mounted on a control and drive box for the pistons.
  • the assembly can be carried out by screwing, or even by ultrasonic welding if the three parts are made of synthetic material. These three parts form an independent functional cassette, which must be able to be sterilized, in particular by gamma rays, and which can be mounted on a piston control and drive unit which contains, for each dosing assembly, a motor, means for transmitting the movement of the engine to the piston, as well as possibly a programming device.
  • This control unit has a long service life, while the functional cassette is only used during treatment.
  • the medical staff removes the cassette that has just been used, and replaces it, on the control unit, with a new cassette, suitable for the new treatment.
  • the two parts of the piston each have a section which tapers from its free end towards its end fixed to the other part.
  • the annular recess formed between the two parts facing the piston, is used for deformation movements of the membrane when the piston moves inside the metering chamber.
  • the waterproofing membrane is made of a material which does not have excellent flexibility, it is preformed in order, prior to its assembly, to present at each piston a hollow part with a profile corresponding to that of a inclined area of a piston part and the assembly area of the two piston parts.
  • the membrane tends to tilt, inside the metering cylinder, between two equilibrium positions corresponding respectively to the retracted position and to the advanced position of the piston. It is thus possible to substantially imitate the residual volume inside the piston.
  • the infusion pump shown in Figure 1, is intended to carry four different liquids. It comprises a box 2 containing means for programming the flow of each of the four liquids, and for corresponding control of the pistons of the metering devices. This box also contains electric batteries for powering the motors ensuring the displacement of the piston rods.
  • a cassette 3 which corresponds to the part ensuring the aspiration of each liquid inside a container constituted for example by a plastic bag, a bottle comprising a socket. air or a syringe, and the discharge of this liquid in a tube connected by a catheter to the patient's body.
  • This cassette consists of a stack of three parallelepipedic pieces, for example of polycarbonate, namely a first central piece 4 comprising four metering cylinders 5 , a second piece 6 equipped with four connections A , B , C , and D intended for the connection of the four receptacles in which the liquids to be transferred are located, and a third part 7 in which are provided bores 8 corresponding to the metering cylinders 5 , and serving for the passage of the means for actuating the pistons, which will be described later, these actuating means being shown diagrammatically in the drawing by rods 9 .
  • each lumen 10 which opens into the assembly face with the second part 6 .
  • Each lumen 10 is associated with a discharge tube 12 , the tubes 12 being, in the embodiment shown in FIG. 2, grouped two by two, so that the metering cylinders receiving the liquids from the tubes A and B comprise slots 10 which are grouped together at an outlet S1 , while the inlet pipes C and D correspond to metering cylinders and lights whose pipes 12 are grouped together at an outlet S2 .
  • Figures 7 and 8 show alternative embodiments of the part 4 , in which the connections between the outlet pipes 12 are different.
  • the outlet tubing S1 corresponds only to the inlet A , the outlet S2 resulting from the assembly of the outlet tubings corresponding to the liquids supplied by the fittings B , C and D.
  • each of the inlet pipes A , B , C , D supplying a specific liquid is associated with an outlet pipe, respectively S1 , S2 , S3 and S4 .
  • the second part 6 comprises, opposite each metering cylinder 5 , a cavity 13 of diameter greater than that of the corresponding cylinder 5 , and communicating with a container for supplying liquid by one of the pipes, respectively A , B , C and D.
  • This cavity serves as a housing for a disc 14 the face of which, facing the metering cylinder, is stepped.
  • This cylinder comprises a large diameter part capable of bearing against the first part 4 , beyond the metering cylinder 5 , extended in its central part and on the side of the metering cylinder by a cylindrical part 15 of diameter less than that of the cylinder.
  • Through holes 16 are formed in the external part of the disc 14 , and open opposite the metering cylinder 5 .
  • the disc 14 is subjected to the action of a spring 17 which pushes it opposite the metering cylinder 5 .
  • the assembly of parts 4 and 6 is carried out with the interposition of a deformable membrane 18 , produced for example from polyethylene, polypropylene, or polytetrafluoroethylene.
  • a deformable membrane 18 produced for example from polyethylene, polypropylene, or polytetrafluoroethylene.
  • pins forming spacers not shown in the drawing, which pass through the membrane 18 .
  • the membrane 18 In its part located opposite the center of each metering cylinder, the membrane 18 has an orifice 19 .
  • the assembly between the first part 4 and the third part 7 is carried out with the interposition of a sealing membrane 20 .
  • a piston coupled to the rod 9 is mounted at each metering cylinder 5 and the corresponding bore 8.
  • This piston is made in two parts 22 and 23 assembled to each other by a screw 24 for example, the part 22 being disposed inside the metering chamber 5 , and part 23 being disposed, on the other side of the sealing membrane 20 , inside the bore 8 .
  • the piston part 22 is made of a material compatible with the liquid which has to pass through the pump, while the piston part 23 can be made of a material which is not compatible with such a liquid, but having other qualities, such as that of allow easy attachment to the drive rod 9 .
  • the piston part 23 can be made of a ferromagnetic material, and that the drive rod 9 can be equipped with a magnet 25 allowing instant fixing and disassembly of the rod and the piston , respectively during the joining and detaching of the cassette 3 and of the housing 2 .
  • the two parts 22 and 23 of the piston each have a section which narrows from its free end towards its end fixed on the other part, which leads to the provision of an annular recess 26 , intended to facilitate the deformation of the sealing membrane 20 during the displacement of the piston.
  • the waterproofing membrane can be made of polyethylene, polypropylene, polytetrafluoroethylene, polyester or a fabric reinforced with elastomer.
  • the membrane 20 does not have perfect flexibility, it is advantageous to preform it, by giving it a shape corresponding to the profile of one of the inclined zones of the piston, and of the zone of assembly between the two parts. piston.
  • the assembly between the different parts 4 , 6 , 7 with the interposition of the membranes 18 and 20 can be achieved for example by screwing using screws 27 in the embodiment shown in the drawing, it being specified that the structure in synthetic material of parts 4 , 6 and 7 allows their assembly by welding, for example by ultrasound.
  • Figures 3 to 6 show the operating mode of this pump, for a metering cylinder.
  • the piston is in the low position, and the metering cylinder 5 is filled with liquid.
  • the piston 22 , 23 is moved in a direction of reduction of the volume of the cylinder, the pressure exerted by the liquid on the membrane, on the one hand, intimately applies the latter against the disc 14 , preventing any passage of liquid from the chamber to the supply and, on the other hand, ensures lifting partial of the disc 14 against the action of the spring 17 , allowing a sufficient deformation of the membrane to allow the passage of the liquid from the metering cylinder 5 into the corresponding lumen 10 , the liquid being evacuated from this lumen by the tubing 12 .
  • This phenomenon is illustrated by arrows in Figure 4.
  • FIG. 4 also shows the deformation of the sealing membrane 20 during the displacement of the piston, and illustrates well the fact that after a rounded deformation of FIG. 4, the membrane resumes, at the end of the piston stroke, a position stable, as shown in figure 5 which is the inverse of the starting position corresponding to figure 3.
  • Figure 5 shows the upper end of the piston stroke, which it is remarkable to note that it corresponds to a very reduced dead volume.
  • a vacuum is created inside the metering cylinder 5 , which causes a deformation of the membrane towards the interior of this metering cylinder, ensuring detachment of the membrane vis-à-vis the central part 15 of the disc 14 , allowing the passage of liquid from the cavity 13 , through the through holes 16 , between the disc 14 and the member 18 , then through the orifice 19 of the membrane 18 , for filling the metering cylinder 5 .
  • the movement illustrated in FIG. 6 continues to the starting position which was illustrated in FIG. 3.
  • the membrane 18 plays, vis-à-vis the metering cylinder 5, both the role of inlet valve and the role of outlet valve.
  • the device due to the presence of the disc 14 , the device has any guarantee of use in the event of an overpressure at the inlet, since this overpressure can in no case result in an increase in flow rate which may be harmful for the patient.
  • the invention brings a great improvement to the existing technique by providing an infusion pump, in particular for ambulatory treatment, of very simple structure, of high reliability, and capable of undergoing modifications with a view to its adaptation to the type of treatment, keeping the same housing, the same structure for parts 6 and 7 at the end of the cassette by adapting the part central 4 , both with regard to its thickness to modify the volume of the metering chamber, as regards the arrangement of the outlet conduits with a view to grouping or not the outlets of the liquids to be infused.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Vascular Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)
  • Reciprocating Pumps (AREA)
  • Fluid-Pressure Circuits (AREA)
  • External Artificial Organs (AREA)

Claims (9)

  1. Flüssigmedikamenteninfusionspumpe, umfassend wenigstens eine Zylinder- Kolbenvorrichtung zum Ansaugen einer Flüssigkeit in einen Behälter und zum Wiederausstoßen derselben in einen mit dem Patienten verbundenen Rohransatz, dadurch gekennzeichnet, daß sie umfaßt:
    - Ein erstes Teil (4), in dem wenigstens ein Dosierzylinder (5) angeordnet ist, der einen durch alternierende Bewegung angeregten Kolben (22, 23) beinhaltet und in eine der Seiten des Teils orthogonal zu dieser Seite einmündet;
    - ein zweites Teil (6), das auf der Seite des ersten Teils (4) aufliegt, in welche jeder Zylinder (5) einmündet, das jedem Zylinder (5) gegenüberliegend einen Hohlraum (13) umfaßt, dessen Durchmesser größer ist als jener des entsprechenden Zylinders, und das mit einem Versorgungsbehälter für Flüssigkeit in Verbindung steht;
    - eine dichte und elastisch deformierbare Membran (18), welche zwischen den beiden Teilen (4, 6) eingespannt ist und jedem Zylinder (5) gegenüberliegend eine Öffnung (19) umfaßt;
    - in jedem Hohlraum (13) des zweiten Teiles (6) aufgenommen eine Scheibe (14), deren zum ersten Teil (4) zugewandte Seite gestuft ist und einen äußeren Abschnitt umfaßt, der über die Membran auf der Seite des ersten Teiles aufliegt, in welche der entsprechende Zylinder einmündet, und zwar gerade um diesen Zylinder herum, und einen zentralen Abschnitt (15) umfaßt, der auf der Seite des Innenraumes des Zylinders vorspringt, wobei diese Scheibe Durchgangslöcher (16) umfaßt, die gleichmäßig verteilt und in der Nähe ihres Umfangs angeordnet sind;
    - eine Feder (17), die einen Druck auf die Scheibe in Richtung des ersten Teiles ausübt; und
    - jedem Zylinder (5) zugeordnet ein Einlaß (10), der in die gleiche Seite des ersten Teils (4) einmündet wie der betrachtete Zylinder (5), wobei dieser Einlaß (10), einem in diesen Teil ausgebildeten Austragsrohransatz zugeordnet, dem gleichen Hohlraum (13) wie der Zylinder gegenüberliegend in der Nähe dieses Zylinders (5) angeordnet ist, aber jenseits der Scheibe (14), die diesen Hohlraum enthält, und das von der zwischen den beiden Teilen eingespannten Membran (18) bedeckt ist.
  2. Pumpe nach Anspruch 1, dadurch gekennzeichnet, daß die Scheibe (14), die in dem Hohlraum (13) des zweiten Teiles (6) angeordnet ist, einen zylindrischen Abschnitt mit großem Durchmesser umfaßt, der in seinem zentralen Abschnitt auf Seiten des Dosierungszylinders durch einen zylindrischen Abschnitt (15) verlängert ist, dessen Durchmesser kleiner ist als jener des Zylinders (5), wobei die Durchgangslöcher (16) in dem äußeren Abschnitt angeordnet sind und in den gegenüberstehenden-Zylinder (5) münden.
  3. Pumpe nach einem der Ansprüche 1 und 2, dadurch gekennzeichnet, daß sie ein drittes Teil (7) beinhaltet, das mit dem ersten Teil (4) auf der dem zweiten Teil (6) entgegengesetzten Seite in Kontakt steht und Ausnehmungen (8) umfaßt, die die Zylinder (5) des ersten Teiles verlängern, wobei eine Abdichtungsmembran (20) zwischen dem ersten Teil (4) und dem dritten Teil (7) eingespannt angebracht ist, wobei der Kolben jeder Pumpe zwei Elemente (22, 23) umfaßt, die miteinander verbunden und zu beiden Seiten der Abdichtungsmembran (20) angeordnet sind, wobei jenes im Zylinder Angeordnete (22) aus einem Material gefertigt ist, das sich mit der zu fördernden Flüssigkeit verträgt, und wobei das andere Element (23) zur Befestigung von Antriebsmitteln (9) des Kolbens bestimmt ist.
  4. Pumpe nach Anspruch 3, dadurch gekennzeichnet, daß das Kolbenelement (23), das auf Seiten des dritten Teils (7) angeordnet ist, aus einem ferromagnetischen Material hergestellt ist, das zur Befestigung an dem magnetischen Ende eines Bewegungsantriebsschaftes (9) bestimmt ist.
  5. Pumpe nach einem der Ansprüche 3 und 4, dadurch gekennzeichnet, daß die beiden Elemente (22, 23) des Kolbens jeweils einen Abschnitt aufweisen, der sich von dessen freiem Ende zu dessen am anderen Element befestigten Ende hin verjüngt.
  6. Pumpe nach Anspruch 5, dadurch gekennzeichnet, daß die Abdichtungsmembran (20) vorgeformt ist, um vor ihrer Montage im Bereich jedes Kolbens einen Hohlabschnitt mit einem Profil aufzuweisen, das jenem eines geneigten Bereichs eines Kolbenelementes und des Verbindungsbereichs der beiden Kolbenelemente entspricht.
  7. Pumpe nach einem der Ansprüche 1-6, dadurch gekennzeichnet, daß sie Nocken oder andere Zwischenstücke umfaßt, welche Abstandshalter zwischen dem ersten und dem zweiten Teil bilden, um die Druckverformung der zwischen ihnen angeordneten Membran zu kalibrieren.
  8. Pumpe nach einem der Ansprüche 3-7, dadurch gekennzeichnet, daß die drei Teile (4, 6, 7) und die zwischen ihnen angeordneten Membranen miteinander zusammengebaut sind und eine abnehmbare Funktionseinheit (3) bilden, die zur abnehmbaren Anbringung auf einem Gehäuse (2) zur Steuerung und zum Antrieb der Kolben bestimmt ist.
  9. Pumpe nach Anspruch 8, dadurch gekennzeichnet, daß sie Unverwechselbarkeitselemente umfaßt, die den Montagemitteln des Gehäuses und der die Zylinder beinhaltenden Funktionseinheit zugeordnet sind.
EP93906662A 1992-03-24 1993-03-24 Medikamenteninfusionspumpe Expired - Lifetime EP0632732B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9203775 1992-03-24
FR9203775A FR2689014B1 (fr) 1992-03-24 1992-03-24 Pompe de perfusion de liquides medicaux.
PCT/FR1993/000296 WO1993018806A1 (fr) 1992-03-24 1993-03-24 Pompe de perfusion de liquides medicaux

Publications (2)

Publication Number Publication Date
EP0632732A1 EP0632732A1 (de) 1995-01-11
EP0632732B1 true EP0632732B1 (de) 1996-01-03

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EP93906662A Expired - Lifetime EP0632732B1 (de) 1992-03-24 1993-03-24 Medikamenteninfusionspumpe

Country Status (12)

Country Link
US (1) US5503538A (de)
EP (1) EP0632732B1 (de)
JP (1) JP3009468B2 (de)
AT (1) ATE132376T1 (de)
AU (1) AU669888B2 (de)
CA (1) CA2129512C (de)
DE (1) DE69301236T2 (de)
DK (1) DK0632732T3 (de)
ES (1) ES2081709T3 (de)
FR (1) FR2689014B1 (de)
GR (1) GR3018682T3 (de)
WO (1) WO1993018806A1 (de)

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US9555186B2 (en) 2012-06-05 2017-01-31 Tandem Diabetes Care, Inc. Infusion pump system with disposable cartridge having pressure venting and pressure feedback
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EP3146211A4 (de) * 2014-05-20 2018-02-14 Ying Lin Cai Exzenter-rondellstruktur für komprimierende membranpumpe mit mehrfachwirkung
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FR1403779A (fr) * 1964-05-14 1965-06-25 Tech Et Commerciale Du Motocyc Dispositif de membrane-clapet pour les pompes de lave-glace des véhicules automobiles
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US4545735A (en) * 1984-08-17 1985-10-08 Uniroyal, Ltd. Diaphragm pump having a valve sheet with inlet and outlet flaps and having antisiphoning capability during pump shutdown
DE3515624A1 (de) * 1985-04-30 1986-11-27 Karl Dipl.-Phys. 8520 Erlangen Prestele Medikamentendosiergeraet mit einem hauptspeicher und einer dosierkammer
US4646781A (en) * 1985-05-07 1987-03-03 Pacesetter Infusion, Ltd. Diaphragm valve for medication infusion pump
DE8901872U1 (de) * 1989-02-17 1990-06-21 Knf Neuberger Gmbh, 7800 Freiburg, De
DE8901972U1 (de) * 1989-02-20 1989-05-24 Felten & Guilleaume Energietechnik Ag, 5000 Koeln, De
US5344292A (en) * 1992-08-20 1994-09-06 Ryder International Corporation Fluid pumping system and apparatus

Also Published As

Publication number Publication date
DK0632732T3 (da) 1996-03-04
FR2689014B1 (fr) 1994-06-03
GR3018682T3 (en) 1996-04-30
DE69301236T2 (de) 1996-05-15
CA2129512A1 (fr) 1993-09-30
WO1993018806A1 (fr) 1993-09-30
US5503538A (en) 1996-04-02
EP0632732A1 (de) 1995-01-11
AU3757993A (en) 1993-10-21
CA2129512C (fr) 1997-07-08
JP3009468B2 (ja) 2000-02-14
AU669888B2 (en) 1996-06-27
ES2081709T3 (es) 1996-03-16
ATE132376T1 (de) 1996-01-15
DE69301236D1 (de) 1996-02-15
JPH08500744A (ja) 1996-01-30
FR2689014A1 (fr) 1993-10-01

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